From Pyrazolones to Azaindoles: Evolution of Active-Site SHP2 Inhibitors Based on Scaffold Hopping and Bioisosteric Replacement.
Antineoplastic Agents
/ chemical synthesis
Catalytic Domain
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Screening Assays, Antitumor
Enzyme Inhibitors
/ chemical synthesis
Humans
Indoles
/ chemical synthesis
MAP Kinase Signaling System
/ drug effects
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Protein Binding
Protein Tyrosine Phosphatase, Non-Receptor Type 11
/ antagonists & inhibitors
Pyrazolones
/ chemical synthesis
Structure-Activity Relationship
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
10 12 2020
10 12 2020
Historique:
pubmed:
20
11
2020
medline:
4
2
2021
entrez:
19
11
2020
Statut:
ppublish
Résumé
The tyrosine phosphatase SHP2 controls the activity of pivotal signaling pathways, including MAPK, JAK-STAT, and PI3K-Akt. Aberrant SHP2 activity leads to uncontrolled cell proliferation, tumorigenesis, and metastasis. SHP2 signaling was recently linked to drug resistance against cancer medications such as MEK and BRAF inhibitors. In this work, we present the development of a novel class of azaindole SHP2 inhibitors. We applied scaffold hopping and bioisosteric replacement concepts to eliminate unwanted structural motifs and to improve the inhibitor characteristics of the previously reported pyrazolone SHP2 inhibitors. The most potent azaindole
Identifiants
pubmed: 33210922
doi: 10.1021/acs.jmedchem.0c01265
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Indoles
0
Pyrazolones
0
PTPN11 protein, human
EC 3.1.3.48
Protein Tyrosine Phosphatase, Non-Receptor Type 11
EC 3.1.3.48
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM